rs111033290

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The ENST00000409709.9(MYO7A):c.2187+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,612,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

MYO7A
ENST00000409709.9 splice_donor

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 9.49

Variant links:

Genes affected

MYO7A (HGNC:7606): (myosin VIIA) This gene is a member of the myosin gene family. Myosins are mechanochemical proteins characterized by the presence of a motor domain, an actin-binding domain, a neck domain that interacts with other proteins, and a tail domain that serves as an anchor. This gene encodes an unconventional myosin with a very short tail. Defects in this gene are associated with the mouse shaker-1 phenotype and the human Usher syndrome 1B which are characterized by deafness, reduced vestibular function, and (in human) retinal degeneration. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

MYO7A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.013838748 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-77175465-G-A is Pathogenic according to our data. Variant chr11-77175465-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77175465-G-A is described in Lovd as [Pathogenic]. Variant chr11-77175465-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4 linkuse as main transcript	c.2187+1G>A		splice_donor_variant		ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9 linkuse as main transcript	c.2187+1G>A		splice_donor_variant		1	NM_000260.4	ENSP00000386331		Q13402-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000201

AC:

AN:

248786

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135084

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000398

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1460736

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

726674

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000612

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000905

Hom.:

Bravo

AF:

0.0000264

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jun 08, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2017	The c.2187+1 G>A splice site variant has been previously reported in association with Usher syndrome (Adato et al., 1997). This variant destroys the canonical splice donor site in intron 18, and is expected to cause abnormal gene splicing. The variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). In summary, we consider this variant to be likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 07, 2018	The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. The best available variant frequency is uninformative because it is below the disease allele frequency. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 14, 2023	This sequence change affects a donor splice site in intron 18 of the MYO7A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYO7A are known to be pathogenic (PMID: 8900236, 25404053). This variant is present in population databases (rs111033290, gnomAD 0.03%). Disruption of this splice site has been observed in individuals with Usher syndrome type I (PMID: 9382091, 19074810). This variant is also known as IVS18 +1G>A. ClinVar contains an entry for this variant (Variation ID: 43175). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Usher syndrome type 1

Pathogenic:2

Pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 05, 2022	NM_000260.3(MYO7A):c.2187+1G>A is a canonical splice variant classified as pathogenic in the context of MYO7A-related disorders. c.2187+1G>A has been observed in cases with relevant disease (PMID: 9382091, 19074810, 33111345). Functional assessments of this variant are not available in the literature. c.2187+1G>A has been observed in population frequency databases (gnomAD: ASJ 0.04%). In summary, NM_000260.3(MYO7A):c.2187+1G>A is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Nonsyndromic genetic hearing loss

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

May 21, 2020

A heterozygous canonical splice site variant was identified, NM_000260.3(MYO7A):c.2187+1G>A in intron 18 of 48 of the MYO7A gene. The nucleotide at this position has very high conservation (PhyloP, UCSC). In silico software predicts this variant to cause aberrant splicing (NetGene2, NNSPLICE, Human Splicing Finder), however, , RNA studies are required to determine if splicing is altered. The variant is present in the gnomAD population database at a frequency of 0.002% (5 heterozygotes; 0 homozygotes). The variant has previously been reported as pathogenic in patients with autosomal recessive Usher syndrome (ClinVar, Adato, A. et al. (1997), Jacobson, S. et al. (2009), Jiang, L. et al. (2015)). A different variant in the same splice site (c.2187+1G>T) has also been shown to cause Usher syndrome (Khalaileh, A. et al. (2018)). A heterozygous canonical splice site variant was identified, NM_000260.3(MYO7A):c.2187+1G>A in intron 18 of 48 of the MYO7A gene. The nucleotide at this position has very high conservation (PhyloP, UCSC). In silico software predicts this variant to cause aberrant splicing (NetGene2, NNSPLICE, Human Splicing Finder). The variant is present in the gnomAD population database at a frequency of 0.002% (5 heterozygotes; 0 homozygotes). The variant has previously been reported as pathogenic in patients with Usher syndrome (ClinVar, Adato, A. et al. (1997), Jacobson, S. et al. (2009), Jiang, L. et al. (2015)). A different variant in the same splice site (c.2187+1G>T) has also been shown to cause Usher syndrome (Khalaileh, A. et al. (2018)). Subsequent analysis of parental samples indicated that this variant was maternally inherited. Based on information available at the time of curation, this variant has been classified as PATHOGENIC. Based on information available at the time of curation, this variant has been classified as PATHOGENIC. -

Usher syndrome type 1;C1832475:Autosomal dominant nonsyndromic hearing loss 11;C1838701:Autosomal recessive nonsyndromic hearing loss 2

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 21, 2021

- -

Rare genetic deafness

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 22, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Uncertain

0.96

MutationTaster

Benign

1.0

D;D;D;D

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_DL_spliceai

1.0

Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over